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Typhoid fever (Enteric fever)
This document provides information about enteric (typhoid) fever, including: - It is caused by the bacterium Salmonella enterica and is a global public health problem affecting millions annually. - Clinical features include prolonged high fever, abdominal discomfort, diarrhea or constipation, and potential complications like intestinal perforation. - Diagnosis involves blood, stool, or bone marrow cultures and serologic tests. Ceftriaxone is the treatment of choice for multidrug-resistant cases. Early diagnosis and appropriate antibiotic treatment are important to prevent complications.
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Typhoid fever (Enteric fever)
- 1. - Dr. LokanadhaReddy M V Consultant Paediatrician Sreenika children’s clinic Bangalore ENTERIC FEVER/TYPHOID FEVER
- 2. Salmonellosis - Why? •Common and widely distributed • Global major public health problem • Affecting millions • Food borne disease • Significant mortality
- 3. ETIOLOGY • Salmonella entericaserovars (Gm -ve) • Typhi (S.Typhi) - Most common • Paratyphi - very similar but less severe • A • B (Schotmulleri) • C (Hirschfeldii) • Disease ratio 10:1 (Typhi : Paratyphi)
- 4. EPIDEMIOLOGY • 26.9 Milliontyphoid cases/year worldwide (80%) • 1% mortality MC in Asia • 5.4 Million paratyphoid cases/year (20%) • 12 Million DALY • More in children < 5 years, of incidence, complications and hospitalisation
- 5. • Gram-Negative FacultativeRods • Family - Enterobacteriaceae, like E.Coli • Habitat - Intestinal tract of warm and cold blooded animals • Causes 2 diseases • Enteric fever - Bloodstream infection • AGE - Food-borne infection MICROBIOLOGY
- 6. Gm -ve Rods Flagellated Motile Produce H2S onthiosulphate
- 7. Enterobactiriaceae • Eschericia Coli •Shigella • Citrobacter Salmonella enterica • Enterica (>99.5%) • Salamae • Arizonae • Diarizonae • Indica • Bongori • Houtenae Family Species Subspecies S.Typhi S.Paratyphi A,B,C Serovars
- 8. Somatic (O) / Cellwall antigens Surface (Envelope) antigens Flagellar (H) antigens Heat stable Alcohol resistant May mask O antigens Heat labile Used for serological studies Vi antigen occurs in only 3 servers Used for serological studies Typhi, Paratyphi C and Dublin Antigenic structure
- 9. Cultures: XLD agar Bloodagar HE agar
- 10. • Exotoxins: Enterotoxin,Cytotoxin have role in diarrhoeal symptoms • Genetics: Plasmids in salmonella code for antibiotic resistance • Most specific gene products - Vi (virulence) polysaccharide capsule, seen in 90% of S.Typhi and has protective effect against bactericidal action of serum of infected patients • Antibiotic susceptibility: Resistance to Ampicillin, streptomycin, chloramphenicol, sulphonamides. Colistin resistance is not yet observed. • DOC till 1972 was chloramphenicol. In 1972 chloramphenicol-resistant strains emerged.
- 11. EPIDEMIOLOGY • Resistant toAmpicillin, chloramphenicol & Cotrimoxazole • Increased resistance to Nalidixic acid (Quinolone) and Fluoroquinolones • Mode of transmission: Ingestion of foods or water contaminated with human feces, seafoods contaminated with sewage water • Risk factors : Antacids, PPI, H2 blockers - reduce infective dose
- 12. PATHOGENESIS Infective dose 105 -109 Gutmucosa - terminal ileum Street food contaminated water M cells, Enterocytes Paracellular route Attaches to microvilli & stays in payers patches Mesenteric lymph nodes Blood (1o Bacteremia) Asymptomatic, B/C -ve Reticuloendothelial system - replicates in macrophages Liver, spleen, GB,BM Blood (2o Bacteremia) Clinical symptoms End of Inc. Period (4-14 days) Down regulates host inflammatory response Re-exp. of PP via Bile Pro-inflam. ck (IL-6,IL-1B,TNF-a) —> Fever Enterotoxin, cytotoxin —> Diarrhoea Host Risk factors : HIV, H.pylori
- 14. PATHOLOGICAL CHANGES INTESTINE: • Hyperplasia ofpayers patches —> subsequent necrosis and sloughing of overlying epithelium —> Ulcers —>heal without scarring or stricture • Occasionally ulcer may penetrate muscularis and serosa causing intestinal perforation MLN, LIVER, SPLEEN: Hyperaemic with focal necrosis BM: Mononuclear response with focal necrosis
- 15. CLINICAL FEATURES • IP: 7-14 days (3-30 days) • Mild illness : Low-grade fever, malaise, slight dry cough • Severe illness : Abdominal discomfort and complications • Factors influencing severity : Duration of illness before initiating correct therapy, choice of antibiotics, age, previous exposure or vaccine, virulence of strain, infective dose, host immune factors • More dramatic presentation & complications in < 5 years • Infancy : Diarrhoea, toxicity, DIC, more fatality • Rare in children : Relative bradycardia, neurologic manifestations, GI bleeding (common in adults)
- 16.
- 17. CLINICAL FEATURES • Fever: Prolonged High grade (up to 105’F) with chills and rigors, Initially low-grade at onset and rises gradually, classic step ladder pattern is rare. Child is not active during inter-febrile period. Unlike viral fever which peaks at the onset of fever. • Rash : 25% have macular or maculopapular rash (rose spots) - 7th-10th day (2nd week), in crops of 10-15 on lower chest and abdomen, lasting 2-3 days • Hepatosplenomegaly : seen in 35% cases and 15% cases respectively • Malaise, dull headache, anorexia, nausea, abdominal discomfort, coated tongue • Bronchitis like picture in early days with rhonchi and crepitations
- 18. CLINICAL FEATURES • Diarrhoea:With fever is a common presentation, classical pea soup diarrhoea seen in early days. • Later constipation ensues with mild abdominal distension, diffuse tenderness and paralytic ileus. Early constipation may be due to obstruction of hypertrophied payer’s patches. • Atypical presentation in malaria endemic areas • Multidrug-resistant Typhoid : more severe, more toxicity, complications and mortality • Usually resolves in 2-4 weeks • Drug-resistant Paratyphoid also can be severe
- 19. COMPLICATIONS • LIVER: Alteredliver function is seen in many but clinically significant jaundice, hepatitis and cholecystitis are rare and a/w adverse outcomes • INTESTINE: Hemorrhage (<1%) and perforation (0.5- 1%) are rare in children. Seen in 2nd-3rd week • Perforation -> markedly increased abdominal pain(RLQ), tenderness, vomiting, peritonitis features like Tachycardia, hypotension, rigidity, guarding. Rising TLC, left shift and free air in AXR are seen. • TOXIC MYOCARDITIS: Rare, a/w arrhythmias, Sinoatrial block, cariogenic shock
- 20. COMPLICATIONS • CNS: uncommonin children. Delirium, psychosis, raised ICT, Acute cerebellar ataxia, chorea, deafness, GBS. Mortality is more(50%) but recovery is complete with no sequelae. Called severe or complicated enteric fever. • OTHERS: Fatal BM necrosis, DIC, HUS, pyelonephritis, nephrotic syndrome, meningitis, endocarditis, parotitis, orchitis, suppurative lymphadenitis • CARRIER: Chronic carrier rates lower in children
- 22. DIAGNOSIS • BLOOD CULTURE:Gold standard, positive in 40- 60% cases in 1st week. Sensitivity 90% in 1st week to 40% in 4th week. Bile-broth media/BACTEC. Sufficient blood 10ml in adults/5ml in children in 1:5 ratio of blood: media to be collected • STOOL CULTURE: Positive after 1st week. Occasionally positive in incubation period • URINE CULTURE : Positive after 1st week • BONE MARROW CULTURE: More sensitive but invasive, may help in PUO evaluation
- 23. DIAGNOSIS • CBC: • TLC:Frequently low in relation to fever and toxicity like 4000- 5000 cells/uL, but a wide range is seen. In younger children leukocytosis is common up to 20,000-25,000 cells/uL • Eosinopenia, Neutrophilic predominance can be there • PLT : Usually normal. Thrombocytopenia + Anemia is a marker of severe illness and a/w DIC • CRP : High, vs Low in dengue/viral fevers • LFT : may be deranged but significant hepatic dysfunction/jaundice is rare. AST/ALT may rise to 2-3 times
- 24. DIAGNOSIS • WIDAL TEST: Measures antibodies against O and H antigens. Becomes positive after 5 days of fever • Lacks sensitivity and specificity in endemic areas • Many false-positive and false-negatives occur • Diagnosis of typhoid on widal alone is prone to error • O titres - 1:160 -> acute enteric fever (appears early) • H titres - 1: 160 -> Past infection/immunised(positive in recovery) • Rising titres to four-fold are significant but its time-consuming process • Positive results may represent previous infection • Widal does not access Vi Antigens, so its not false positive for newer vaccines but may be for classical TA vaccine.
- 25. DIAGNOSIS • TYPHIDOT: • Adot ELISA kit that detects IgM and IgG antibodies to OMP- outer membrane protein • Becomes positive in 2-3 days • Sensitivity - 100% and specificity - 80% • Limitation: Only Qualitative not quantitative like widal test IgM IgG Interpretation + + Acute enteric fever + - Early acute infection - + Past infection
- 26. DIAGNOSIS • Newer testsusing MABs directly detect S.Typhi specific antigens in serum or Vi Ag in urine. These are not proved efficient. • Nested PCR using H1-d primers is promising and provides rapid diagnosis. • “BASU” - Blood culture, Agglutination (widal) test, Stool culture and Urine culture in 1st, 2nd, 3rd and 4th weeks.
- 27. DIFFERENTIAL DIAGNOSIS • ACUTE GASTRO-ENTERITIS •BRONCHITIS, BRONCHO-PNEUMONIA • MALARIA • SEPSIS • TUBERCULOSIS, BRUCELLOSIS, LEPTOSPITOSIS • VIRAL FEVERS, DENGUE, ACUTE HEPATITIS, INFECTIOUS MONONUCLEOSUS
- 28. TREATMENT • Early diagnosisand appropriate treatment • Vast majority can be managed at home with oral antibiotics and close follow-up for complications or failure of response to Rx • Hospitalisation and IV antibiotics : Persistent vomiting, severe diarrhoea, abdominal distension • Adequate Rest, Hydration and correction of fluid and electrolyte imbalance.
- 29. TREATMENT • ISOLATION :should be nursed with precautions • ANTIPYRETICS : Paracetamol 10-15mg/kg PO every 4-6 Hours. Ibuprofen can be used. Salicylates are contraindicated - shock. • DIET : Soft, easily digestible diet except in abdominal distension or ileus • ANTIBIOTICS : Critical to minimise complications • STEROIDS: Dexa 3mg/kg ->1mg/kg Q6H x 48 hrs only in cases of severely ill with shock, (CNS signs) obtundation, stupor or coma. May mask abdominal signs.
- 31. TREATMENT • CEFTRIAXONE : •DOC for MDR typhoid as it is common • Start 75-100 mg/kg/day OD/BD x 5-7 days • Once afebrile, change to oral Cefixime x 10 days • Superior to Cefotaxime because of its biliary excretion (kills bacteria in GB)
- 32. TREATMENT • CEFIXIME : •20 mg/kg/day in two doses orally x 10-14 days for mild cases • Can be used as follow up Rx for IV Ceftriaxone • As a rule 1st/2nd gen. cephalosporins and aminoglycosides are not useful in treatment
- 33. TREATMENT • CHLORAMPHENICOL : •50 mg/kg/day orally x 14 days in areas without resistant bacteria • IV is given only if oral intake is not possible as 75mg/kg/day • SE: Bone marrow suppression rarely. Undetectable reticulocytes gives the clue. “Gray baby syndrome”. • Afebrile within 7 days of Rx • If no response then unlikely to respond to Ampicillin, Amoxicillin, Cotrimoxazole • Used apart from Aztreonam/Cotrimoxazole, in patients with penicillin or ceftriaxone allergy.
- 34. TREATMENT • CIPROFLOXACIN : •DOC for Adults and Children >12 years • < 12 years can be given if ceftriaxone fails or in life-threatening cases • Dosage: IV 20 mg/kg/day Q8-12H x 7-10 days • Relatively safe in children • If culture shows sensitivity to be downgraded to cipro because of lower relapse rates • AZITHROMYCIN : • 20 mg/kg/day (double dose) x 5 days
- 35. PRACTICAL TIPS • Asa general rule treatment (Ceftraixone) is until 5-7 days after defervescence • For any Rx response is slow and takes 3-7 days • Do not give laxatives or enema for constipation -can cause perforation • Add Metronidazole and Aminoglycoside if perforation or peritonitis is suspected • Osteomyelitis or Meningitis - Rx for 4-6 weeks
- 36. PRACTICAL TIPS • Ifeosinophils appear which were absent earlier, indicates recovery • Recovery signs : Subjective improvement, less toxic, improved appetite, general feeling better, improved feel of abdomen - soft and not distended, increasing interval between fever spikes, fever responding better and faster to antipyretics, lower fever spikes than earlier. • If two antibiotics fail consider MDR typhoid. Stop the antibiotic and observe for 2-3 days if child is not toxic and ill. • Repeat physical examination, CBC, CXR may help in difficult cases
- 37. PROGNOSIS • Depends onage, early diagnosis and appropriate Rx, general health, nutrition salmonella serotype and complications • RELAPSE: Despite App. Rx 5-15% may have relapse after initial clinical response. Milder illness. More with cephalosporins than with Fluoroquinolones/Azithromycin • Chronic Carriers : who excrete S.Typhi > 3 mo. <2% in children and increases with age. • Rx : Amoxicillin (100 mg/kg/day) with probenecid (30 mg/ kg/day) or cotrimoxazole (10 mg/kg/day) for 6-12 weeks is recommended. If the strain is nalidixic acid sensitive, quinolones for 28 days is better • A chronic urinary carrier is seen in schistosomiasis
- 38. • REFERENCES • Nelson’sTextbook of pediatrics - 20th Edition • OP Ghai Textbook of pediatrics - 8th Edition • Santosh kumar manual of pediatric practice - 4th Edition • Amdekar Lessons from grand rounds 2 • Todar’s textbook of bacteriology - online edition